PROJECT SUMMARY Chronic and severe worry is a key characteristic of Anxiety Disorders (AD), which have the highest prevalence across the lifespan, typically start in childhood and adolescence, and increase risk for depression and suicide during adolescence. Chronic severe worry is also transdiagnostic and has been associated with increased risk of onset, relapse, and treatment resistance in mood disorders in adolescents. Yet, little is known about the neural mechanisms of worry that may contribute to onset of mood disorders. Neuroimaging studies in adults indicate that chronic severe worry is associated with deficits in frontolimbic networks, which undergo important maturational changes in adolescence. Our preliminary fMRI findings in older adults with severe worry show heightened activation in limbic/paralimbic structures during worry induction as well as reduced connectivity be- tween regions of the Salience Network (SN) and the Executive Control Network (ECN) and heightened amyg- dala-paraventricular nucleus (PVN) connectivity during worry reappraisal. Based on findings in depression, such patterns of neural function could represent a neural marker linking chronic worry with increased risk for depression. However, it remains unclear whether these patterns observed in older adults translate in anxious adolescents and young adults and whether they vary with age and sex. Furthermore, given evidence that anxi- ety may be associated with an imbalance in ?-aminobutyrate (GABA) and glutamatergic systems and that these systems undergo important maturational changes during adolescence and early adulthood, we will ex- amine the functioning of these systems as they relate to worry regulation in anxious individuals. This R21 pro- posal will serve to seed a larger, longitudinal R01 proposal that will test an overarching hypothesis that severe worry has distinct and cumulative age-related consequences due to altered neurodevelopment of the coordina- tion within and between neural regions within the SN and ECN in adolescence. These alterations contribute to increases in chronic arousal, ineffective emotion regulation, and lead to outcomes such as depression. Partici- pants will include 40 mid-/late-pubertal adolescents (12-17 yrs; 20 females) and 40 young adults (18-30 yrs; 20 females), recruited transdiagnostically based on worry severity, with 2/3 reporting severe levels of worry. Par- ticipants will complete psychiatric assessments, a worry induction and reappraisal fMRI task and a resting state session. To characterize the molecular underpinnings of frontolimbic networks, we will also acquire novel mag- netic resonance spectroscopy imaging measures of brain metabolites relevant to anxiety (e.g., GABA and glu- tamate) in the prefrontal cortical and limbic/paralimbic subcortical regions. The study aims to characterize age- related patterns of neural activation and functional connectivity during worry induction and regulation and to determine the extent to which GABA and glutamate concentrations are associated with neural functioning and worry and anxiety symptoms. Findings could lead to the identification of targets for novel neurodevelopmental- ly-based interventions of chronic and severe worry and prevention of depression in at-risk individuals.